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Updated: Nov 3, 2025
Detection of a Circulating MicroRNA Custom Panel in Patients with Metastatic Colorectal Cancer
Published on: March 14, 2019
Molecular and Radiological Features of Microsatellite Stable Colorectal Cancer Cases With Dramatic Responses to
Bridget P Keenan1, Katherine VAN Loon1, Anuradha D Khilnani2
1Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, U.S.A.
Background/Aim:
The majority of colorectal cancer (CRC) cases, which are microsatellite stable (MSS) and do not harbor mismatch repair deficiency/microsatellite instability, are resistant to immunotherapy. Identification of patients with exceptional responses in MSS CRC and predictive biomarkers is an unmet need that needs to be addressed.
Case Report:
We report three cases of MSS CRC with durable clinical benefit from immunotherapy with anti-PD-1 checkpoint inhibitors. Two cases bear a POLE P286R mutation, which has been associated with lack of immunotherapy response in MSS CRC. Two cases bear alterations in Ataxia-Telangiectasia Mutated (ATM) which may contribute to observed responses, including interaction with a co-administered intratumoral stimulator of interferon genes (STING) pathway agonist in one patient.
Conclusion:
Novel DNA damage repair alterations, including mutations in ATM, can provide insight into additional mechanisms by which genomic alterations can sensitize MSS CRC to diverse immunotherapies.
Insights
Microsatellite stable colorectal cancer (MSS CRC) is typically immunotherapy-resistant. Novel DNA repair alterations, like ATM mutations, may sensitize MSS CRC to immunotherapy, offering new treatment avenues.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Microsatellite stable colorectal cancer (MSS CRC) represents the majority of cases but exhibits resistance to current immunotherapy strategies.
- Identifying predictive biomarkers for exceptional responders in MSS CRC is a critical unmet clinical need.
- Understanding resistance mechanisms is key to developing more effective immunotherapies for MSS CRC.
Observation:
- Three cases of MSS CRC demonstrated durable clinical benefit from anti-PD-1 checkpoint inhibitor immunotherapy.
- Two of these patients had a POLE P286R mutation, a marker previously linked to immunotherapy non-response.
- Two patients presented with alterations in the Ataxia-Telangiectasia Mutated (ATM) gene, potentially contributing to their response.
Findings:
- Germline or somatic alterations in DNA damage repair genes, such as ATM, may overcome immunotherapy resistance in MSS CRC.
- The interplay between ATM alterations and immunotherapy warrants further investigation.
- Concurrent intratumoral stimulator of interferon genes (STING) pathway agonist may enhance responses in patients with ATM alterations.
Implications:
- ATM mutations represent a potential predictive biomarker for immunotherapy response in MSS CRC.
- Targeting DNA damage repair pathways could sensitize MSS CRC to immunotherapy.
- These findings open new avenues for personalized immunotherapy strategies in colorectal cancer.
